Ponatinib in chronic myeloid leukemia (CML): Consensus on patient treatment and management from a European expert panel

Five tyrosine kinase inhibitors (TKIs) are currently approved in the European Union for treatment of chronic myeloid leukemia (CML) and all have considerable overlap in their indications. While disease-specific factors such as CML phase, mutational status, and line of treatment are key to TKI selection, other important features must be considered, such as patient-specific comorbidities and TKI safety profiles. Ponatinib, the TKI most recently approved, has demonstrated efficacy in patients with refractory CML, but is associated with an increased risk of arterial hypertension, sometimes severe, and serious arterial occlusive and venous thromboembolic events. A panel of European experts convened to discuss their clinical experience in managing patients with CML. Based on the panel discussions, scenarios in which a CML patient may be an appropriate candidate for ponatinib therapy are described, including presence of the T315I mutation, resistance to other TKIs without the T315I mutation, and intolerance to other TKIs

A variable probe pitch micro-Hall effect method

Hall effect metrology is important for a detailed characterization of the electronic properties of new materials for nanoscale electronics. The micro-Hall effect (MHE) method, based on micro four-point probes, enables a fast characterization of ultrathin films with minimal sample preparation. Here, we study in detail how the analysis of raw measurement data affects the accuracy of extracted key sample parameters, i.e., how the standard deviation on sheet resistance, carrier mobility and Hall sheet carrier density is affected by the data analysis used. We compare two methods, based primarily on either the sheet resistance signals or the Hall resistance signals, by theoretically analysing the effects of electrode position errors and electrical noise on the standard deviations. We verify the findings with a set of experimental data measured on an ultrashallow junction silicon sample. We find that in presence of significant electrical noise, lower standard deviation is always obtained when the geometrical analysis is based on the sheet resistance signals. The situation is more complicated when electrode position errors are dominant; in that case, the better method depends on the experimental conditions, i.e., the distance between the insulating boundary and the electrodes. Improvement to the accuracy of Hall Effect measurement results is crucial for nanoscale metrology, since surface scattering often leads to low carrier mobility

Early BCR-ABL1 Transcript Decline after 1 Month of Tyrosine Kinase Inhibitor Therapy as an Indicator for Treatment Response in Chronic Myeloid Leukemia

In chronic myeloid leukemia (CML), early treatment prediction is important to identify patients with inferior overall outcomes. We examined the feasibility of using reductions in BCR-ABL1 transcript levels after 1 month of tyrosine kinase inhibitor (TKI) treatment to predict therapy response. Fifty-two first-line TKI-treated CML patients were included (imatinib n = 26, dasatinib n = 21, nilotinib n = 5), and BCR-ABL1 transcript levels were measured at diagnosis (dg) and 1, 3, 6, 12, 18, 24, and 36 months. The fold change of the BCR-ABL1 transcripts at 1 month compared to initial BCR-ABL1 transcript levels was used to indicate early therapy response. In our cohort, 21% of patients had no decrease in BCR-ABL1 transcript levels after 1 month and were classified as poor responders. Surprisingly, these patients had lower BCR-ABL1 transcript levels at dg compared to responders (31% vs. 48%, p = 0.0083). Poor responders also significantly more often had enlarged spleen (55% vs. 15%; p<0.01) and a higher percentage of Ph+ CD34+CD38- cells in the bone marrow (91% vs. 75%, p<0.05). The major molecular response rates were inferior in the poor responders (at 12m 18% vs. 64%, p<0.01; 18m 27% vs. 75%, p<0.01; 24m 55% vs. 87%, p<0.01). In conclusion, early treatment response analysis defines a biologically distinct patient subgroup with inferior long-term outcomes.Peer reviewe

CD36 defines primitive chronic myeloid leukemia cells less responsive to imatinib but vulnerable to antibody-based therapeutic targeting

Tyrosine kinase inhibitors (TKIs) are highly effective for the treatment of chronic myeloid leukemia (CML), but very few patients are cured. The major drawbacks regarding TKIs are their low efficacy in eradicating the leukemic stem cells responsible for disease maintenance and relapse upon drug cessation. Herein, we performed ribonucleic acid sequencing of flow-sorted primitive (CD34(+) CD38(low)) and progenitor (CD34(+) CD38(+)) chronic phase CML cells, and identified transcriptional upregulation of 32 cell surface molecules relative to corresponding normal bone marrow cells. Focusing on novel markers with increased expression on primitive CML cells, we confirmed upregulation of the scavenger receptor CD36 and the leptin receptor by flow cytometry. We also delineate a subpopulation of primitive CML cells expressing CD36 that is less sensitive to imatinib treatment. Using CD36 targeting anti-bodies, we show that the CD36 positive cells can be targeted and killed by antibody-dependent cellular cytotoxicity. In summary, CD36 defines a subpopulation of primitive CML cells with decreased imatinib sensitivity that can be effectively targeted and killed using an anti-CD36 anti-body.Peer reviewe